1. Field of the Invention
The present invention relates to new camptothecin derivatives possessing anti-tumor activity and to a process for preparing such derivatives. More particularly, the present invention relates to new camptothecin derivatives carrying an aminocarbonyloxy group or a chlorocarbonyloxy group in any of the 9-, 10- and 11-positions on the ring A thereof and possessing excellent anti-tumor activity with a low level of toxicity as well as a process for the preparation of the new camptothecin derivatives.
2. Description of the Prior Art
Camptothecin is an alkaloid extracted and isolated from Camptotheca accuminata (Nyssaceae), etc., which has a pentacyclic structure consisting of a characteristic fused 5-ring system consisting of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action, its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itselt for clinical treatments is significantly limited because of high toxicity. Moreover, camptothecin and the majority of derivatives thereof are sparingly soluble in water and thus involve a problem in case of administration as medicaments.
Accordingly, a number of attempts have been made not only to reduce toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives but also to make camptothecin and derivatives thereof easily soluble in water by chemical modifications of the camptothecin molecule or substituents therein. The chemical modifications so far reported are mainly about the ring D and/or E of camptothecin. As a method for making camptothecin or derivatives thereof soluble in water, for example, a ring-opening reaction for the E-ring (lactone ring) of camptothecin was used in the prior arts to form an alkali metal salt of the carboxyl function. However, any chemical modification of the ring D and/or E, including such ring-opening reaction, revealed only failure in maintaining anti-tumor activity and very poor improvement in toxicity [J. Med. Chem., 19 (1976), 675]. From the chemotherapeutic point of view, therefore, it is of importance that the chemical modifications of camptothecin should be restricted in the rings A, B and C without effecting any change in the rings D and E which are believed to be the essential structural elements for the expression of the above mentioned characteristic biological activities.
Except for a method for functionalizing the 12-position of camptothecin reported in 1976 which comprises a series of many troublesome conversion and purification operations starting with a relatively easily operable nitration at the 12-position [P. Pei-chuang et al., Hau Hsueh Hsueh Pao 33 (1975), 71; Chem. Abstr. 84 (1976) 115629p], no success was reported until 1979 in connection with chemical functionalization of camptothecin in a moiety involving the rings A, B and C. This is probably ascribable to the reasons that camptothecin itself is only sparingly soluble in various organic solvents and that camptothecin possessing the molecular nature of heterocyclic rings is resistant to the so-called electronphilic reactions conventionally carried out on aromatic rings. In the present status, such obstacles strongly discourage chemical modifications of camptothecin contemplated academically for preparing new classes of derivatives thereof.
Under the above mentioned circumstances, the present inventors previously found together with co-workers processes for preparing 5- and 7-substituted camptothecins (U.S. Pat. No. 4,399,282) by introducing (1) a hydroxymethyl group into the 7-position of camptothecin by subjecting camptothecin to a radical reaction with methanol by the aid of sulfuric acid and a peroxide, (2) a hydroxy group into the 5-position of camptothecin by treating camptothecin with sulfuric acid, water and a persulfate in the presence of a metal ion or by treating camptothecin with iodine in the presence of a base, and (3) an alkyl or aralkyl group into the 7-position of camptothecin by subjecting camptothecin to a radical reaction with a compound of the general formula: RX ##STR2## preferably in a large excess amount by the aid of sulfuric acid, water and a peroxide in the presence of a metal ion. Further, the present inventors prepared together with co-workers a great number of new camptothecin derivatives from these 5- and 7-substituted camptothecin derivatives (U.S. Pat. Nos. 4,399,276 and 4,399,282) according to the process wherein 7-hydroxymethylcamptothecin is acylated with an acylating agent to obtain 7-acyloxymethylcamptothecins or 20-O-acyl-7-acyloxymethylcamptothecins or wherein 7-hydroxymethylcamptothecin is oxidized with an oxidizing agent usually capable of oxidizing a hydroxymethyl group to a carboxyl group to obtain 7-carboxycamptothecin, which is then esterified with an alcohol to obtain 7-alkoxycarbonylcamptothecins, the process wherein 5-alkoxycamptothecins are obtained by dissolving 5-hydroxycamptothecin in a lower alcohol, adding thereto an acid and heating the mixture, or wherein 5-acyloxycamptothecins or 20-O-acyl-5-acyloxycamptothecins are obtained by acylating 5-hydroxycamptothecin with a reactive acid derivative such as an acid anhydride or a halide of a carboxylic acid, the process wherein camptothecin-7-aldehyde is obtained by treating the 7-hydroxymethylcamptothecin with various cationoid reagents without using any oxidizing agent, and the process wherein 7-alkoxymethylcamptothecins and 7-dialkoxymethylcamptothecins are obtained by treating 7-hydroxymethylcamptothecin in a lower alkanol or an aralkyl alcohol with an acid.
Further successively, the present inventors prepared together with co-workers camptothecin-1-oxide or 7- or 5-substituted derivatives thereof by treating camptothecin or a 7- or 5-substituted derivative thereof with an N-oxidizing agent (Japanese Laid-open Patent Appln. No. 58-39685; U.S. Ser. No. 414,528) as well as various 10-substituted camptothecin derivatives according to the process wherein camptothecin-1-oxide or a 7- or 5-substituted derivative thereof obtained as above is reacted with an active hydrogen-containing reagent in the presence of an acid under irradiation of UV-rays (Japanese Laid-open Patent Appln. No. 58-39683; U.S. Ser. No. 413,879) or the process wherein camptothecin is first catalytically hydrogenated and the resultant 1,2,6,7-tetrahydrocamptothecin is treated with an acylating agent and then with a mixture of nitric acid and sulfuric acid to form a 1-acyl-10-nitro-1,2,6,7-tetrahydrocamptothecin which is then deacylated and oxidized to 10-nitrocamptothecin and is then modified in various manners known per se to convert the 10-nitro group into other 10-substituents, e.g. 10-hydroxy group (Japanese Laid-open Patent Applns. Nos. 58-134095 and 58-152888; U.S. Ser. No. 413,879).
It was also found that when camptothecin in sulfuric acid was treated carefully with nitric acid under ice-cooling and agitation, new 9-nitrocamptothecin could be obtained in a yield of 30-40% together with the known 12-nitrocamptothecin. This new 9-nitrocamptothecin is then reduced to 9-aminocamptothecin which can be converted into various 9-substituted camptothecin derivatives according to the methods known per se as in the case of 10-nitrocamptothecin (Japanese Laid-open Patent Appln. No. 59-51289). For example, 9-aminocamptothecin can be converted into the corresponding 9-halogeno or 9-cyano derivative by once converting the 9-amino derivative into 9-diazonium salt and then treating the salt with cuprous halide or cyanide according to the Sandmayer reaction. Further, 9-diazonium salt can be converted into 9-hydroxy, 9-alkoxy and 9-acyloxy derivatives in the manner known per se.
Various 11-substituted camptothecin derivatives were prepared by catalytically hydrogenating camptothecin to form 1,2,6,7-tetrahydrocamptothecin, treating this tetrahydro derivative directly with sulfuric acid and nitric acid whereby the 11-position of camptothecin was selectively nitrified to form 11-nitro-1,2,6,7-tetrahydrocamptothecin, oxidizing the 11-nitro- 1,2,6,7-tetrahydrocamptothecin to 11-nitrocamptothecin, and thereafter converting the 11-nitro group in the resultant compound into various 11-substituents, as in the case of 10-nitrocamptothecin, according to the methods known per se (Japanese Laid-open Patent Appln. No. 59-51987). For example, the 11-nitro group thus formed can first be converted into an 11-amino group by reduction according to Clemensen or the like method and the latter 11-amino group can further be converted into an 11-hydroxy group by diazotization with a nitrite under cooling and acidic conditions followed by hydrolysis under warming and weakly alkaline conditions.
From the studies on various camptothecin derivatives prepared heretofore, the present inventors obtained an interesting result that introduction of an alkyl group into the 7-position of camptothecin tends to enhance anti-tumor activity while introduction of a hydroxyl group into the ring A of camptothecin tends to reduce toxicity without sacrificing the anti-tumor activity. For further extensive researches based on this interesting result for clarifying the relation between the substituents and locations thereof in camptothecin structure and pharmacological properties including toxicity, therefore, there is still a great demand in this art for developing further new classes of camptothecin derivatives carrying various substituents especially in 7-position and on the ring A of camptothecin skeleton.